基于孟德尔随机化的维生素 D 对缺血性脑卒中二级预防作用的研究
Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke.
机构信息
Division of Cardiology, Queen Mary Hospital (Y.-H.C., J.J.H., Y.-K.W., K.-W.A., H.-F.T.), The University of Hong Kong, Hong Kong SAR, China.
School of Public Health (C.M.S., J.Z., S.-L.A.Y., T.-H.L.), The University of Hong Kong, Hong Kong SAR, China.
出版信息
Stroke. 2021 Dec;52(12):3926-3937. doi: 10.1161/STROKEAHA.120.032634. Epub 2021 Sep 27.
BACKGROUND AND PURPOSE
Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction.
METHODS
Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study-identified genetic variants of Vit-D mechanistic pathways (, , and ; F statistic, 73; <0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach.
RESULTS
In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; =0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48-0.81]; <0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35-0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42-0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30-0.81]).
CONCLUSIONS
Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.
背景与目的
实验研究表明，维生素 D（Vit-D）可以促进血管再生和修复。先前的随机研究主要集中在一级预防上。Vit-D 是否可以预防有过缺血性损伤的患者再次发生缺血性中风和心肌梗死尚不清楚。在这里，我们通过孟德尔随机化方法分析了 Vit-D 对复发性缺血性中风和心肌梗死的二级预防作用。
方法
基于通过高通量外显子组芯片筛选来自一个衍生队列样本的 12 个 Vit-D 机制途径的先前全基因组关联研究确定的遗传变异（n=5331，45% Vit-D 缺乏，89% 基因分型）构建的 Vit-D 的遗传风险评分（，，和 ；F 统计量，73；<0.001），我们通过两样本、个体数据、前瞻性孟德尔随机化方法在一个具有明确缺血性疾病的独立亚组（n=441，均有过首次缺血性事件；随访时间，41.6±14.3 年）中对已建立的缺血性疾病患者的心肌梗死（MI）和缺血性中风的复发进行了集中分析。
结果
在缺血性疾病亚组中，11.1%（n=49/441）发生了复发性缺血性中风或 MI，13.3%（n=58/441）发生了复发性或新发缺血性中风/ MI。Kaplan-Meier 分析显示，遗传风险评分预测了从复发性缺血性中风或 MI 中无事件的生存时间（对数秩，13.0；=0.001）。Cox 回归显示，遗传风险评分独立预测了复发性缺血性中风或 MI 联合事件的风险降低（风险比，0.62 [95%CI，0.48-0.81]；<0.001），在调整了潜在混杂因素后。孟德尔随机化支持 Vit-D 对复发性缺血性中风或 MI（Wald 估计值：比值比，0.55 [95%CI，0.35-0.81]）和任何复发性或新发缺血性中风/ MI（比值比，0.64 [95%CI，0.42-0.91]）以及单独的复发性 MI（比值比，0.52 [95%CI，0.30-0.81]）的主要终点具有因果保护作用。
结论
遗传预测 Vit-D 水平降低与有过缺血性中风或 MI 的患者的缺血性血管事件复发有关。
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